Drug-induced steatohepatitis

ABSTRACT

Introduction: Drug induced steatohepatitis (DISH), a form of drug induced liver injury (DILI) is characterized by intracellular accumulation of lipids in hepatocytes and subsequent inflammatory events, in some ways similar to the pathology seen with other metabolic, viral and genetic causes of non alcoholic fatty liver disease and steatohepatitis (NAFLD and NASH).

Areas covered: This paper provides a comprehensive review of the main underlying mechanisms by which various drugs cause DISH, and outlines existing preclinical tools to predict it and study underlying pathways involved. The translational hurdles of these models are discussed, with the example of an organotypic liver system designed to address them. Finally, we describe the clinical assessment and management of DISH.

Expert Opinion: The complexity of the interconnected mechanistic pathways underlying DISH makes it important that preclinical evaluation of drugs is done in a physiologically and metabolically relevant context. Advanced organotypic tissue models, coupled with translational functional biomarkers and next-generational pan-omic measurements, may offer the best shot at gathering mechanistic knowledge and potential of a drug causing steatohepatitis. Ultimately this information could also help predict, detect or guide the development of specific treatments for DISH, which is an unmet need as of today.

KEYWORDS:

• Drug-induced steatohepatitis
• liver
• organotypic
• DILI
• NASH

Article highlights

• Drug induced steatohepatitis (DISH) is increasingly important due to the high background of metabolic disease in the population.

• Mechanisms causing DISH are complex due to involvement of multiple cell types and sequential metabolic and inflammatory steps followed by cellular responses.

• Predicting and avoiding DISH pre-clinically is challenging due to limitations of existing models and endpoints.

• More physiological models and translational biomarkers and assays may support discovery of newer management approaches for detection and treatment of DISH.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

Part of the data presented in the paper was funded by National Institutes of Health and National Institute of Diabetes and Digestive and Kidney Diseases grant R44 DK091104.